Migraine is among the world's most disabling illnesses. About 28 million Americans have severe, disabling migraine headaches, and it is expensive to both employers and migraine sufferers, with yearly cost to employers being about $13 billion and yearly medical costs exceeding $1 billion. Trigemina Inc. has pioneered a novel intranasal delivery of antinociceptive peptides for the treatment of migraine and other facial and head pain. To this end, we funded a phase 2 clinical trial to examine the efficacy of intranasal administration of the peptide oxytocin for treatment of migraine. The results of the clinical trial were encouraging, but inconclusive. Another endogenous neuropeptide with antinociceptive activity is the 17 amino acid peptide in the opioid peptide family, nociceptin/orphanin FQ (N/OFQ). This peptide is found in the trigeminal ganglia, and levels are decreased in the blood of migraine patients. Although nociceptive when administered intracerebroventricularly (i.c.v.) we have hypothesized that intranasal delivery will induce the peptide to concentrate in the trigeminal ganglia and reduce painful stimuli induced by migraine or other head or facial pain. Specific Aim 1 will determine the tissue and brain localization of [3H]N/OFQ after intranasal administration. Specific Aim 2 will test the efficacy of intranasal N/OFQ, as well as a high affinity and long lasting analog, in two animal models of head pain or headache. These results will be compared with the efficacy of systemic administration of the high efficacy analgesic morphine, and the primary migraine treatment sumitriptan. Specific Aim 3 will test additional behavioral actions of intranasal N/OFQ to determine whether sedation or other side effects might compromise the desirable actions of N/OFQ. These studies will lead to a better understanding of the potential usefulness of N/OFQ for treatment of migraine and other trigeminal mediated pain syndromes. The fact that N/OFQ is an endogenous compound should facilitate the testing in people and ultimate clinical use. PUBLIC HEALTH RELEVANCE: Migraine can be a severe debilitating syndrome that affects far more women than men. About 28 million Americans have disabling migraine headaches, with a cost to employers of about $13 billion annually with yearly medical costs exceeding $1 billion. Although there are a range of migraine treatments, they are not sufficiently effective on a third of the population. Nociceptin (N/OFQ) is an endogenous neuropeptide that can have analgesic activity when administered appropriately. This project will examine the efficacy of intranasally administered N/OFQ in animal models of migraine and head pain. These studies will provide evidence as to whether intranasal N/OFQ has potential as migraine medication.